When a normal cell loses the ability to control its growth and division it is considered cancerous. Cancers or neoplasms have been reported from every tissue and cell type. These various cancers are normally treated using radiological and/or chemotherapeutic agents. These agents include a wide range of compounds and radioisotopes that work by various mechanisms. Although development has been directed toward agents capable of selective actions on neoplastic tissues, those available presently manifest significant toxicity on normal tissues as a major complication of therapy.
One class of antineoplastic agents is antimetabolites. A further subclass of antimetabolites includes inhibitors of DNA and RNA synthesis and inhibitors of nucleotide synthesis. Many of these are analogs of the naturally occurring nucleosides: adenosine; guanosine; uridine; cytidine; and thymidine. As these nucleoside analogs are inhibitors of DNA and/or RNA synthesis or nucleoside metabolism; these compounds are also useful for treating viral diseases like, including but not limited to, viral hepatitis, AIDS, common cold, rhinitis, and flu. However, their actions on the normal tissues result in side effects, including, but not limited to, anemia, leucopenia, neutropenia, thrombocytopenia, proteinuria, hematuria, vomiting, pain, fever, rash, dyspnea, constipation, diarrhea, hemorrhage, infection, alopecia, stomatitis, somnolence, paresthesias, chemical arachnoiditis, and neurotoxicity. Adverse events may include death. Thus, there is need in the art to provide improved nucleoside analogs for treatment of these diseases.
Additionally, Hepatitis C virus infection is one of the leading causes of chronic liver disease; more than 170 million people worldwide are infected, with HCV genotype 1 predominating in the US. The current standard of treatment consists of PEGylated interferon-α2 (pegIFN) alone or in combination with ribavirin. Combination treatment is effective in only 50% of patients with HCV genotype 1 infection, and some patients experience significant side effects in response to the treatment. Thus, there is considerable interest in the development of more effective agents with fewer side effects.
The present invention seeks to address these and other needs in the art by providing (among other things) a conjugate of a water-soluble, non-peptidic oligomer and nucleoside phosphate.